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Keys to the rapid antidepressant action of ketamine
Ketamine is a clinically used “dissociative analgesic” for pain management and a rapidly acting antidepressant for patients that have not responded to other treatments. Ketamine enhances the activity of AMPA-type glutamate receptors. Zhang et al. showed that this is an indirect effect, involving inhibition of presynaptic NMDA receptors and reduced activity of HCN1 (hyperpolarization-activated cyclic nucleotide–gated channel 1). Ketamine stimulated the phosphorylation of the GluA1 subunit of the postsynaptic AMPA receptors, and mice with a form of this subunit that lacked the phosphorylation site exhibited neither the electrophysiological effects of ketamine nor the antidepressant effects of ketamine. Ketamine was ineffective in changing behavioral responses in mice lacking presynaptic CA3 NMDA receptors or HCN1 channels, and the electrophysiological analysis indicated that ketamine inhibited presynaptic NMDA receptors to reduce HCN1 function, which would promote glutamate release and increase AMPA receptor phosphorylation and activity. This study puts the mechanism of ketamine action on the presynaptic side of the synapse.
